Coatings for drug delivery devices

ABSTRACT

A polymer coating for medical devices based on a polyolefin derivative. A variety of polymers are described to make coatings for medical devices, particularly, for drug delivery stents. The polymers include homo-, co-, and terpolymers having at least one olefin-derived unit and at least one unit derived from vinyl alcohol, allyl alcohol and derivatives thereof.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to a field of medical devices, especiallythe devices used for delivery of drugs. More particularly, it isdirected to coatings for drug delivery devices, such as, for instance,drug eluting vascular stents.

[0003] 2. Description of Related Art

[0004] In the field of medical technology, there is frequently anecessity to administer drugs locally. To provide an efficaciousconcentration to the treatment site, systemic administration of suchmedication often produces adverse or toxic side effect for the patient.Local delivery is a preferred method in that smaller total levels ofmedication are administered in comparison to systemic dosages, but areconcentrated at a specific site. Thus, local delivery produces fewerside effects and achieves more effective results.

[0005] One commonly applied technique for local delivery of the drug isthrough the use of medicated stents. One method of medicating a stent iswith the use of a polymer coating impregnated with the drug.

[0006] References describe a variety of polymers which can be used tocoat stents. Of particular interest is a copolymer of ethylene and vinylalcohol, also known as poly(ethylene-co-vinyl alcohol) or EVOH.Poly(ethylene-co-vinyl alcohol) is also known under the trade name EVALand is distributed commercially by Aldrich Chemical Company ofMilwaukee, Wis. EVAL is also manufactured by EVAL Company of America ofLisle, Ill.

[0007] EVAL is a product of hydrolysis of ethylene-vinyl acetatecopolymers. Those having ordinary skill in the art of polymer chemistrywill understand that EVAL may also be a terpolymer and may include up to5% (molar) of units derived from styrene, propylene and other suitableunsaturated monomers. EVAL possesses a desirable impermeability tooxygen, bio- and blood-compatibility. EVAL is at least somewhathydrophobic and thus is somewhat insensitive to moisture.

[0008] While EVAL has been shown to be a very inert and biocompatiblepolymer which is quite suitable for use with medical vascular devices,some of its properties can be improved. In particular, EVAL, due to ahigh concentration of hydroxyl groups in the vinyl component-derivedunits of the macromolecule, has strong interchain hydrogen bonding,which makes the polymer initially hard to dissolve in an organicsolvent.

[0009] Accordingly, EVAL's solubility in organic solvents is limited. Atthe same time, these hydroxyl groups are responsible for insufficientwater resistance, and in many applications EVAL does absorb more waterthan desired.

[0010] EVAL also has a high degree of crystallinity, due to the presenceof the units of the macromolecule derived from the ethylene component,and a limited ability to fully control the release of drugs. EVAL'slimited ability to fully control the release rate of some drugs below acertain molecular size stems from an insufficient degree ofhydrophobicity of EVAL. This leads to a level of water absorption thatcauses the polymer to swell, increasing the polymer's porosity, and thediffusivity of the drug.

[0011] An improvement over EVAL is desired, so that the polymer formingthe stent coating has a higher degree of hydrophobicity and a lowerdegree of crystallinity as compared to EVAL.

[0012] In view of the foregoing, it is very desirable to havealternative polymeric materials suitable for the use with variousmedical devices, particularly, with stents for controlled drug delivery.These polymeric materials should be bio- and blood-compatible, at leastpartially impermeable to oxygen, melt-processable, have reducedcrystallinity, high hydrophobicity, high tensile strength andflexibility, ability to provide slower drug release rates, and besoluble in organic solvents.

[0013] The present invention provides a number of such polymersaccording to the following description.

SUMMARY

[0014] The embodiments of this invention provide a number of polymers tobe used in coatings with medical devices, particularly, with stents forcontrolled local delivery of drugs. The drugs to be delivered aregenerally incorporated into the coatings.

[0015] The polymers used in the embodiments of this invention can bedivided into several categories. The first category includes copolymersof an olefin, typically, ethylene (but also propylene) with a vinylcomponent containing a hydroxymethyl group. These vinyl components arederivatives of allyl alcohol. Examples of the polymers in this categoryinclude poly(ethylene-co-allyl alcohol), a terpolymerpoly(ethylene-co-allyl alcohol-co-vinyl alcohol),poly(propylene-co-allyl alcohol), poly(ethylene-co-methallyl alcohol), aterpolymer poly(propylene-co-allyl alcohol-co-vinyl alcohol), andpoly(propylene-co-methallyl alcohol).

[0016] The second category includes polymers having units derived fromvinyl alcohol, but no units derived from allyl alcohol. This groupincludes poly(propylene-co-vinyl alcohol), poly(ethylene-co-methvinylalcohol), poly(propylene-co-methvinyl alcohol), and a terpolymerpoly(propylene-co-ethylene-co-vinyl alcohol).

[0017] Finally, the third category includes a homopolymer polyallylalcohol.

[0018] In addition, the embodiments of this invention provide for anumber of coatings fabricated from a variety of terpolymers. Theterpolymers are obtained by co-polymerization of an olefin componentwith a hydroxyl-containing component. These terpolymers are discussed indetail below.

[0019] When a coating is made out of one of the polymers describedabove, a drug to be delivered in a localized fashion is incorporatedinto the coating. Examples of the drugs include antiproliferativesubstances such as actinomycin D, or derivatives and analogs thereof.

[0020] The active agent can also fall under the genus of antineoplastic,anti-inflammatory, antiplatelet, anticoagulant, antifibrin,antithrombin, antimitotic, antibiotic, antiallergic and/or antioxidantsubstances. Particular examples of these and other usable drugs andactive agents are provided below.

[0021] The drug is typically incorporated into a coating matrix on adrug delivery stent, the coating made out of one of the polymersprovided in the embodiments of this invention. In addition, the coatingscan be used on the stent as a primer, rate release limiting membrane,and/or biocompatible topcoat.

[0022] According to one aspect of this invention, a coating for medicaldevices is provided, the coating comprising a polymer having a formula—[CH₂—CHR¹]_(m)—[CH₂—CR²(CH₂OH)]_(n)—[CH₂—CH(OH)_(x)]_(o), wherein R¹and R² is each selected, independently, from a group consisting ofhydrogen and an alkyl group; m and n is each, independently, an integerwithin a range of between about 30 and about 7,600; o is an integerwithin a range of between 0 and about 7,600; and x equals 1 if o equalsat least 1. When R¹ or R² or both is an alkyl group, the alkyl group istypically, but not necessarily, a methyl group.

[0023] According to another aspect of this invention, a coating formedical devices is provided, the coating comprising a polymer having aformula —[CH₂—CH(CH₃)]_(p)—[CH₂—CR³(OH)]_(q)—[CH₂—CH(CH₂OH)_(y)]_(r)—,wherein R³ is selected from a group consisting of hydrogen, and an alkylgroup; p and q is each, independently, an integer within a range ofbetween about 30 and about 7,600; r is an integer within a range ofbetween 0 and about 7,600; and y equals 1 if r equals at least 1. As inthe previous aspect of this invention, when R³ is an alkyl group, thealkyl group is typically, but not necessarily, a methyl group.

[0024] According to yet another aspect of this invention, a coating formedical devices is provided, the coating comprising a polymer selectedfrom a group consisting of poly(ethylene-co-α-methvinyl alcohol),poly(propylene-co-ethylene-co-vinyl alcohol), and polyallyl alcohol.

[0025] According to another aspect of this invention, a coating formedical devices is provided, the coating comprising a polymer, thepolymer being a terpolymer comprising one or more units derived from anolefin and one or more units derived from an unsaturated hydroxylatedmonomer.

[0026] According to another aspect of this invention, a polymer coatingfor medical devices is provided, the coating comprising a polyolefinderivative.

[0027] According to yet another aspect of this invention, a polymericfilm-former for coatings for medical devices is provided, the polymercomprising a polyolefin.

DETAILED DESCRIPTION

[0028] A family of polymers used to make coatings for medical devices,in particular, for drug delivery stents is characterized by the presenceof a polyolefin backbone, pendant on which are alkyl, hydroxyl, and/orhydroxyalkyl groups.

[0029] It is known, that while EVAL has good oxygen-barrier propertiesand some resistance to water vapor, as well as good biocompatibility,its solubility in organic solvents and its ability to provide slow drugrelease are limited. These drawbacks are caused by the strong hydrogenbonding between the hydroxyl groups, which makes the polymer initiallyhard to dissolve in a solvent, but which also leads to swelling of thepolymer in water.

[0030] All polymers disclosed below are somewhat related to EVAL, buthave better properties for the purposes of making coatings for medicaldevices. Particularly, they possess a higher degree of hydrophobicityand lower degree of crystallinity as compared to EVAL.

[0031] The reason for such improved properties is that, compared withEVAL, the polymers can be more hydrophobic, lowering the degree of waterswelling. The polymers can also be more readily dissolved in organicsolvents by having less hydrogen bonding, due to a lower hydroxylcontent, and less crystallinity.

[0032] Improved hydrophobicity of these polymers lowers the equilibriumwater absorption, allowing slower drug release than what is possible forof EVAL.

[0033] For a polymer to be useful in a coating for a drug deliverydevice, it should satisfy at least the following requirements. It shouldabsorb not more than about 5% of water (by weight). It should have anultimate tensile strength of at least 3,500 psi (about 24.2 MPa), and,at the same time, an ultimate elongation to failure exceeding 30%. Itshould be soluble in at least some organic solvents even if those asstrong as dimethylsulfoxide (DMSO) are required. Generally, it should bepossible to make at least a 2% (by weight) solution of the polymer in asolvent, such as DMSO, DMAC, DMF, methanol, toluene, isopropyl alcohol,trifluoroethanol, hexafluoroisopropanol, and similar solvents.

[0034] All the polymers, copolymers and terpolymers according to theembodiments of this invention described below satisfy these criteria.

[0035] The following examples show the polymers, copolymers, andterpolymers used to make coatings for medical devices of the presentinvention.

EXAMPLE 1 Poly(ethylene-co-allyl Alcohol)

[0036] This polymer has the formula:—[CH₂—CH₂]_(m)—[CH₂—CH(CH₂OH)]_(n)—.

[0037] The polymer is synthesized by free radical co-polymerization ofethylene and methyl acrylate followed by treatment of the resultingpoly(ethylene-co-methyl acrylate) with a strong reducing agent, forinstance, a metal hydride. As a result of the reaction of reduction, thehydroxymethyl group of allyl alcohol is formed.

[0038] The polymer can also be synthesized by polymerization of ethylenewith acrylic acid followed by reduction. Free radical polymerization ofallyl acetate with ethylene followed by base hydrolysis results in thesame polymer. This last reaction scheme has the advantage of not usingcostly metal hydride reagents. The process of free radicalpolymerization, metal hydride reduction, and base hydrolysis mentionedabove are known to those having ordinary skill in the art.

[0039] The resulting polymer, poly(ethylene-co-allyl alcohol), is morehydrophobic and thus more soluble in organic solvents than EVAL and itcan be used to form coatings on medical devices.

EXAMPLE 2 Poly(ethylene-co-allyl Alcohol-co-vinyl Alcohol)

[0040] The polymer has the following formula:—[CH₂—CH₂]_(m)—[CH₂—CH(CH₂OH)]_(n)—[CH₂—CH(OH)]_(o)—. This terpolymercan be synthesized from several different sets of starting monomers.Ethylene, methyl acrylate and vinyl acetate can be copolymerized by freeradical initiators, followed by reduction with a strong reducing agent,such as a metal hydride, for instance, lithium aluminum hydride(LiAlH₄). Similarly, ethylene, allyl acetate, and vinyl acetate could bepolymerized and reduced to yield the same product.

[0041] Alternatively, ethylene, allyl acetate, and vinyl acetate couldbe copolymerized and the alcohol groups then formed by catalytic basehydrolysis of the acetate moieties. Lastly, the free radicalpolymerization product of ethylene, methylacrylate and vinyl acetate canfirst be base hydrolyzed to the corresponding alcohol and carboxylgroups. Hydride reduction of the carboxyl group completes the synthesisand requires less hydride reagent than that required in the firstreaction scheme.

EXAMPLE 3 Poly(propylene-co-vinyl Alcohol)

[0042] The polymer has the formula —[CH₂—CH(CH₃)]_(m)—[CH₂—CH(OH)]_(n)—.This polymer is synthesized in a way similar to the synthesis of EVAL,except instead of ethylene, propylene is copolymerized in the usualfashion, by a free radical process with vinyl acetate, followed byhydrolysis of the acetate groups of the resulting copolymer. The processis understood by those having ordinary skill in the art. The finalproduct is very likely to be atactic, with a crystallinity adjustable byvarying the monomer ratios, and thus has a higher solubility in organicsolvents than EVAL.

EXAMPLE 4 Poly(propylene-co-allyl Alcohol)

[0043] The polymer has the formula—[CH₂—CH(CH₃)]_(m)[CH₂—CH(CH₂OH)]_(n)—. This polymer is synthesized in away similar to the synthesis of poly(ethylene-co-allyl alcohol)described in the Example 1, above, only here a poly(propylene-co-methylacrylate) precursor is used instead of poly(ethylene-co-methyl acrylate)precursor of the Example 1.

EXAMPLE 5 Poly(propylene-co-allyl Alcohol-co-vinyl Alcohol).

[0044] The polymer has the formula:—[CH₂—CH(CH₃)]_(m)—[CH₂—CH(OH)]_(n)—[CH₂—CH(CH₂OH)]_(o)—.

[0045] This terpolymer is synthesized in a manner similar to what isdescribed in Example 2, above. Of course, instead of ethylene, propyleneis used here at the stage of copolymerization.

EXAMPLE 6 Poly(ethylene-co-methallyl Alcohol)

[0046] The polymer has the formula—[CH₂—CH₂]_(m)—[CH₂—C(CH₃)(CH₂OH)]_(n)—. The precursor used to fabricatethis polymer is the copolymer of ethylene and methacrylic acid. Thesynthesis of this polymer is achieved by reduction of the carboxyl groupof the precursor to the hydroxyl group. A second synthetic pathway wouldbe co-polymerization of ethylene and methyl methacrylate followed byreduction.

EXAMPLE 7 Poly(propylene-co-methallyl Alcohol)

[0047] The polymer has the formula—[CH₂—CH(CH₃)]_(m)—[CH₂—C(CH₃)(CH₂OH)]_(n)—. It is synthesized in amanner similar to the synthesis of poly(ethylene-co-methallyl alcohol),described in Example 6, above, except instead of thepoly(ethylene-co-methacrylic acid) precursor used in Example 6, apoly(propylene-co-methacrylic acid) precursor is used.

EXAMPLE 8 Poly(ethylene-co-methvinyl Alcohol)

[0048] The polymer has the formula —[CH₂—CH₂]_(m)—[CH₂—C(CH₃)(OH)]_(n)—.This polymer has a structure very similar to that of EVAL, the onlydifference being that the carbon in EVAL which bears the hydroxyl groupis also substituted with a methyl group. Consequently, the properties ofthis copolymer are similar to those of EVAL. However, it can bebeneficially distinguished from EVAL in that its solubility in organicsolvents, due to the presence of an extra methyl group, is better thatthe solubility of EVAL.

[0049] This copolymer can be synthesized by saponification of theacetate groups of a poly(ethylene-co-methvinyl acetate) (also known aspoly(ethylene-co-isopropenyl acetate)) precursor. The preparation ofthis precursor as well as the saponification are conducted in a commonmanner known to those skilled in the art.

EXAMPLE 9 Poly(propylene-co-methvinyl Alcohol)

[0050] The polymer has the formula—[CH₂—CH(CH₃)]_(m)—[CH₂—C(CH₃)(OH)]_(n)—. This polymer is anticipated tohave an amorphous structure due to the presence of atactic propylenegroups. Its synthesis is analogous to that of poly(ethylene-co-methvinylalcohol) described in Example 8, above. The synthesis here involves thesaponification of the acetate groups of a poly(propylene-co-methvinylacetate) precursor according to usual methods known to persons havingordinary skill in the art of polymer chemistry.

EXAMPLE 10 Poly(propylene-co-ethylene-co-vinyl Alcohol)

[0051] The polymer has the formula:—[CH₂—CH(CH₃)]_(m)—[CH₂—CH₂]_(n)—[CH₂—CH(OH)]_(o)—. This terpolymer madeby substituting some of the ethylene in the current synthesis of EVALwith propylene. This leads to lower crystallinity and increasedhydrophobicity of this polymer as compared to EVAL, while retaining allbeneficial properties of EVAL.

EXAMPLE 11 Polyallyl Alcohol

[0052] This homopolymer has the formula —[CH₂—CH(CH₂OH)]_(m)—. It can besynthesized in any common way known to those having ordinary skill inthe art, including free radical polymerization of allyl alcohol.However, polyallyl alcohol is not easily synthesized from allyl alcoholto high molecular weight by conventional free radical polymerizationtechniques due to degradative chain transfer reactions.

[0053] One technique disclosed in the U.S. Pat. No. 3,285,897 toSullivan, et. al. utilizes polymerization at high pressure in thepresence of a free radical polymerization catalyst. U.S. Pat. No.6,096,393 to Ikeda, et. al. discloses several synthetic pathwaysincluding free radical polymerization of methacrylic acid or methylmethacrylate followed by reduction with a metal hydride.

[0054] Polyallyl alcohol is hydrophobic and not soluble in water, but issoluble in some rather strong organic solvents, such as dioxane,tetrahydrofuran, or methanol. Its oxygen barrier properties areexcellent.

[0055] In general, for any polymer, copolymer, or terpolymer discussedin Examples 1-11 above, as the content of the olefinic moiety in thepolymer, copolymer, or terpolymer increases, its elongation to failurealso increases, while both its capacity to absorb water and its ultimatetensile strength decrease.

[0056] In order to achieve the desired water absorption as well asdesired mechanical properties (ultimate tensile strength, elongation tofailure) and solubility, the ratio of monomers is adjusted to yield apolymer having the properties in the desired range. Accordingly, theratios for the monomers used to obtain polymers, copolymers, andterploymers of Examples 1-11 should be within a range as shown inTable 1. TABLE 1 Compositions of (Co)polymers of Examples 1-11. Ex-ample No. Monomer 1 Monomer 2 Monomer 3 Total 1 Ethylene Allyl AlcoholNone m + n = m = 30-7,600 n = 30-7,600 = 300-8,400 2 Ethylene AllylAlcohol Vinyl Alcohol m + n + o = m = 30-7,600 n = 30-7,600 o = 30-7,600= 600-4,200 3 Propylene Vinyl Alcohol None m + n = m = 30-7,600 n =30-7,600 = 300-8,400 4 Propylene Allyl Alcohol None m + n = m = 30-7,600n = 30-7,600 = 300-8,400 5 Propylene Allyl Alcohol Vinyl Alcohol m + n +o = m = 30-7,600 n = 30-7,600 o = 30-7,600 = 300-8,400 6 EthyleneMethallyl None m + n = m = 30-7,600 Alcohol = 300-8,400 n = 30-7,600 7Propylene Methallyl None m + n = m = 30-7,600 Alcohol = 300-8,400 n =30-7,600 8 Ethylene Methvinyl None m + n = m = 30-7,600 Alcohol =300-8,400 n = 30-7,600 9 Propylene Methvinyl None m + n = m = 30-7,600Alcohol = 300-8,400 n = 30-7,600 10 Propylene Ethylene Vinyl Alcohol m +n + o = m = 30-7,600 n = 30-7,600 o = 60-3,800 = 300-8,400 11 Allylalcohol None None n = 30- 7,600

[0057] In addition to the above-discussed eleven examples describingembodiments of this invention, there exist a large number of polymersthat can be also used to make coatings for medical instruments,particularly, for controlled drug delivery stents.

[0058] Such polymers comprise products of copolymerization of an olefinco-monomer component and a hydroxylated monounsaturated co-monomercomponent. Typically, one of the olefin components is mixed andco-polymerized with any two of the hydroxylated components, or viceversa, one of the hydroxylated components is mixed and co-polymerizedwith any two of the olefin components.

[0059] The process of co-polymerization usually involves a free radicalco-polymerization, but any other otherwise acceptable method ofco-polymerization known to those skilled in the art can be used as well.A large number of terpolymers is, thus, available as a result.

[0060] Examples of an olefin component comprise ethylene, propylene, andany butene. Generally, any olefin, straight-chained or branched, havingbetween two and eight carbons can be used. Using olefins with largernumber of carbon atoms is not advisable because polymerization will bedifficult since the reactivity of such olefins will be decreased due totheir increased bulkiness and an increase in steric hindrance.

[0061] Examples of a hydroxylated monounsaturated component includevinyl alcohol and its derivatives (i.e., methvinyl alcohol and thelike), allyl alcohol and its derivatives (i.e., methallyl alcohol andthe like), 1-hydroxy-2-methyl ethylene, 1-hydroxy-2-methyl propene, anda number of butene-ols (i.e., 3-butene-1-ol, 3-butene-2-ol,3-butene-3-ol, 3-butene-4-ol and 2-butene-1-ol).

[0062] Obviously, by matching various combinations of olefiniccomponents with hydroxylated monounsaturated components, a very largenumber of terpolymers may be obtained. The longer and the bulkier thegroups on the polymer backbone, the less is the polymer's tendency tocrystallize. This is a positive feature of such bulkier macromolecules,because their ability to dissolve in organic solvents is increased.

[0063] It should be also borne in mind, than every time a vinyl alcoholgroup is present, it was either created by saponification or reductionof an acetate moiety. Therefore, the polymers having the acetate grouponly partially converted to hydroxyl functionality are also included inthe list of the embodiments discussed above. Obviously, such polymerswill have both acetate and vinyl alcohol groups. In addition to theproducts having vinyl alcohol groups, some other above-mentionedterpolymers are also obtained by saponification of the acetate moieties.Such terpolymers include those based on 3-butene-3-ol, 3-butene-4-ol,and 1-hydroxy-2-methyl-propene.

[0064] A polymer of this invention is used on a medical device,particularly, on a drug delivery stent. The invention is used as acoating matrix on the stent. The coating polymer can have severalfunctions. The coating can be used as a primer, as a matrix carrying thedrug, as a rate release limiting membrane and/or as a bio- and/orblood-compatible topcoat.

[0065] In any of these cases, the coating is applied onto the stent by acommonly used method known to the practitioners of the art, forinstance, by spraying, dipping or molding, as described in Examples 12and 13, below. The drug can be incorporated within the coating, or thedrug can be in a separate layer underneath the coating, or the drug canbe adsorbed onto the surface of the coating.

EXAMPLE 12 Poly(ethylene-co-allyl Alcohol) Based Coating

[0066] Poly(ethylene-co-allyl alcohol), the polymer of Example 1 above,is synthesized with a monomer ratio (by moles) of about 1:1. Themolecular weight of ethylene is 28 and of allyl alcohol—58, and both “m”and “n” are equal to a value of about 870. A number average molecularweight of the polymer is about 75,000. The polymer is dissolved in amixture of solvents comprising 50% of DMSO and 50% of DMAC (by weight)to form a 2% solution (by weight).

[0067] A spray apparatus, such as an EFD 780S spray nozzle with aVALVEMATE 7040 control system, manufactured by EFD, Inc. of EastProvidence, R.I. is used to apply the polymer solution to a stent. TheEFD 780S spray nozzle is an air-assisted external mixing atomizer. Thecomposition is atomized by air and applied to the stent surfaces. Duringthe process of applying the composition, the stent can be optionallyrotated about its longitudinal axis, at a speed of 50 to about 150 rpm.The stent can also be linearly moved along the same axis during theapplication.

[0068] The 2% solution of the polymer is applied to a 13-mm TETRA stent(available from Guidant Corporation) in a series of 10-second passes, todeposit 10 μg of coating per spray pass. Between the spray passes, thestent is dried for 10 seconds using flowing air with a temperature of60° C. Five spray passes are applied to form a 50 μg primer layer,followed by baking the primer layer at 140° C. for 20 one hour.

[0069] A drug containing formulation is prepared comprising 2% of thepolymer, 0.66% of actinomycin D and 97.34% of a mixture of solventscomprising 50% of DMSO and 50% of DMAC. All percentage amounts are byweight. In a manner identical to the application of the primer layer,five spray passes are performed to form a 50 μg drug-polymer layer,followed by baking the drug-polymer layer at 50° C. for 2 hours.

[0070] Finally, a topcoat composition to control the drug release rateis prepared, comprising 2% of the polymer and 98% of a mixture ofsolvents comprising 50% of DMAC, 20% of DMSO and 30% of ethanol. Allpercentage amounts are by weight. In a manner identical to theapplication of the primer layer and the drug-polymer layer, thirty-fivespray passes are performed to form a 350 μg topcoat layer, followed byfinal baking at 50° C. for 2 hours.

EXAMPLE 13 Poly(propylene-co-vinyl Alcohol) Based Coating

[0071] Poly(propylene-co-vinyl alcohol), the polymer of Example 3 above,is synthesized with a monomer ratio of the propylene segments and thevinyl alcohol segments (by moles) of about 44:56. The molecular weightof propylene is 42 and of vinyl alcohol 44. The value for “m” in thepolymer is about 765, and for “n”—about 974. A number average molecularweight of the polymer is about 75,000. The free radical polymerizationresults in the propylene component being atactic. The polymer isdissolved in DMAC to form a 2% solution (by weight).

[0072] Using the process and equipment described in Example 12, above,the 2% solution of the polymer is applied to a 13-mm TETRA stent. Fivespray passes are applied to form a 50 μg primer layer, followed bybaking the primer layer at 140° C. for one hour.

[0073] A drug containing formulation is prepared comprising 2% of thepolymer, 1% of β-estradiol and 97% of DMAC. All percentage amounts areby weight. In a manner identical to the application of the primer layer,thirty spray passes are performed to form a 300 μg drug-polymer layer,followed by baking the drug-polymer layer at 50° C. for 2 hours.

[0074] Finally, a topcoat composition to control the drug release rateis prepared, comprising 2% of the polymer and 98% of a mixture ofsolvents comprising 70% of DMAC and 30% of ethanol. All percentageamounts are by weight. In a manner identical to the application of theprimer layer and the drug-polymer layer, thirty spray passes areperformed to form a 300 μg topcoat layer, followed by final baking at50° C. for 2 hours.

[0075] The stent, or other implantable medical device can be used in anypart of the vascular system, including neurological, carotid, coronary,renal, aortic, iliac, femoral or any other peripheral vascular lumens.The are no limitations on the size of the implantable medical device,its length, diameter, strut thickness or pattern. Examples of suchimplantable devices include self-expandable stents, balloon-expandablestents, stent-grafts, grafts (e.g., aortic grafts), artificial heartvalves, cerebrospinal fluid shunts, coronary shunts, pacemakerelectrodes, and endocardial leads (e.g., FINELINE and ENDOTAK, availablefrom Guidant Corporation). The underlying structure of the device can beof virtually any design. The device can be made of a metallic materialor an alloy such as, but not limited to, cobalt chromium alloy(ELGILOY), stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE(Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy,gold, magnesium, or combinations thereof. “MP35N” and “MP20N” are tradenames for alloys of cobalt, nickel, chromium and molybdenum availablefrom standard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devicesmade from bioabsorbable or biostable polymers could also be used withthe embodiments of the present invention.

[0076] There no limitations on the drugs to be incorporated within thecoating. For example, the active agent of the drug could be designed toinhibit the activity of vascular smooth muscle cells. It can be directedat inhibiting abnormal or inappropriate migration and/or proliferationof smooth muscle cells to inhibit restenosis.

[0077] Generally speaking, the drug can include any substance capable ofexerting a therapeutic or prophylactic effect in the practice of thepresent invention. The drug may include small molecule drugs, peptides,proteins, oligonucleotides, or double-stranded DNA.

[0078] Examples of the drugs which are usable include antiproliferativesubstances such as actinomycin D, or derivatives and analogs thereof.Synonyms of actinomycin D include dactinomycin, actinomycin IV,actinomycin I₁, actinomycin X₁, and actinomycin C₁.

[0079] The active agent can also fall under the genus of antineoplastic,anti-inflammatory, antiplatelet, anticoagulant, antifibrin,antithrombin, antimitotic, antibiotic, antiallergic and antioxidantsubstances. Examples of such antineoplastics and/or antimitotics includepaclitaxel, docetaxel, methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride, and mitomycin.

[0080] Examples of such antiplatelets, anticoagulants, antifibrin, andantithrombins include sodium heparin, low molecular weight heparins,heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin andprostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa plateletmembrane receptor antagonist antibody, recombinant hirudin, andthrombin.

[0081] Examples of such cytostatic or antiproliferative agents includeangiopeptin, angiotensin converting enzyme inhibitors such as captopril,cilazapril or lisinopril, calcium channel blockers (such as nifedipine),colchicine, fibroblast growth factor (FGF) antagonists, fish oil(ω-3-fatty acid), histamine antagonists, lovastatin (an inhibitor ofHMG-COA reductase, a cholesterol lowering drug), monoclonal antibodies(such as those specific for Platelet-Derived Growth Factor (PDGF)receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandininhibitors, suramin, serotonin blockers, steroids, thioproteaseinhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide.

[0082] An example of an antiallergic agent is permirolast potassium.Other therapeutic substances or agents which may be appropriate includealpha-interferon, genetically engineered epithelial cells, rapamycin anddexamethasone.

[0083] Having described the invention in connection with severalembodiments thereof, modification will now suggest itself to thoseskilled in the art. As such, the invention is not to be limited to thedescribed embodiments.

What is claimed is:
 1. A coating for a medical device, said coatingcomprising a polymer having a formula:—[CH₂—CHR¹]_(m)—[CH₂—CR²(CH₂OH)]_(n)—[CH₂—CH(OH)_(x)]_(o)—, wherein R¹is selected from a group consisting of a hydrogen atom and an alkylgroup; and R² is selected from a group consisting of a hydrogen atom andan alkyl group.
 2. The coating of claim 1, wherein said alkyl group ismethyl.
 3. The coating of claim 1, wherein said polymer absorbs not morethan 5% of water by mass.
 4. The coating of claim 1, wherein saidpolymer is soluble in an organic solvent.
 5. The coating of claims 1,wherein said polymer has a tensile strength of not less than about 24MPa (3,500 pounds per square inch).
 6. The coating of claim 1, whereinsaid polymer has an ultimate elongation exceeding 30 percent.
 7. Thecoating of claim 1, wherein said coating is applied on said device as aprimer.
 8. The coating of claim 1, wherein said coating contains a drug.9. The coating of claim 1, wherein said coating is applied on saiddevice as a rate release limiting membrane.
 10. The coating of claim 1,wherein: said m is an integer within a range of between about 30 andabout 7,600; said n is an integer within a range of between about 30 andabout 7,600; said o is an integer within a range of between 0 and about7,600; and said x equals 1 if said o equals at least
 1. 11. The coatingof claim 1, wherein said medical device is a stent.
 12. A coating for amedical device, said coating comprising a polymer having a formula:—[CH₂—CH(CH₃)]_(p)—[CH₂—CR³(OH)]_(q)—[CH₂—CH(CH₂OH)_(y)]_(r)—, whereinR³ is selected from a group consisting of a hydrogen atom and an alkylgroup.
 13. The coating of claim 12, wherein said alkyl group is methyl.14. The coating of claim 12, wherein said polymer absorbs not more than5% of water by mass.
 15. The coating of claim 12, wherein said polymeris soluble in an organic solvent.
 16. The coating of claim 12, whereinsaid polymer has a tensile strength of not less than about 24 MPa (3,500pounds per square inch).
 17. The coating of claim 12, wherein saidpolymer has an ultimate elongation exceeding 30 percent.
 18. The coatingof claim 12, wherein said coating is applied on said device as a primer.19. The coating of claim 12, wherein said coating contains a drug. 20.The coating of claim 12, wherein said coating is applied on said deviceas a rate release limiting membrane.
 21. The coating of claim 12,wherein: said p is an integer within a range of between about 30 andabout 7,600; said q is an integer within a range of between about 30 andabout 7,600; said r is an integer within a range of between 0 and about7,600; and said y equals 1 if said r equals at least
 1. 22. The coatingof claim 12, wherein said medical device is a stent.
 23. A coating for amedical device, said coating comprising a polymer comprisingpoly(ethylene-co-α-methvinyl alcohol),poly(propylene-co-ethylene-co-vinyl alcohol) or polyallyl alcohol. 24.The coating of claim 23, wherein said polymer absorbs not more than 5%of water by mass.
 25. The coating of claim 23, wherein said polymer issoluble in an organic solvent.
 26. The coating of claim 23, wherein saidpolymer has a tensile strength of not less than about 24 MPa (3,500pounds per square inch).
 27. The coating of claim 23, wherein saidpolymer has an ultimate elongation exceeding 30 percent.
 28. The coatingof claim 23, wherein said coating is applied on said device as a primer.29. The coating of claim 23, wherein said coating contains a drug. 30.The coating of claim 23, wherein said coating is applied on said deviceas a rate release limiting membrane.
 31. The coating of claim 23,wherein said medical device is a stent.
 32. A coating for a medicaldevice, said coating comprising a polymer, said polymer being aterpolymer comprising one or more units derived from an olefin and oneor more units derived from an unsaturated hydroxylated monomer.
 33. Thecoating of claim 32, wherein said olefin comprises a C₂-C₈ straightchain or branched olefin.
 34. The coating of claim 32, wherein saidunsaturated hydroxylated monomer is selected from a group consisting ofvinyl acetate, -α-methvinyl alcohol, allyl alcohol, methallyl alcohol,1-hydroxy-2-methyl ethylene, 1-acetoxy-2-methyl propene, 3-butene-1-ol,3-butene-2-ol, 2-butene-1-ol, 3-acetoxy-3-butene, and4-acetoxy-3-butene.
 35. The coating of claim 32, wherein said polymerabsorbs not more than 5% of water by mass.
 36. The coating of claim 32,wherein said polymer is soluble in an organic solvent.
 37. The coatingof claim 32, wherein said polymer has a tensile strength of not lessthan about 24 MPa (3,500 pounds per square inch).
 38. The coating ofclaim 32, wherein said polymer has an ultimate elongation exceeding 30percent.
 39. The coating of claim 32, wherein said coating contains adrug.
 40. The coating of claim 32, wherein said coating is applied onsaid device as a matrix to carry a drug.
 41. The coating of claim 32,wherein said coating is applied on said device as a rate releaselimiting membrane.
 42. The coating of claim 32, wherein said medicaldevice is a stent.
 43. A polymer coating for a medical device, saidcoating comprising a polyolefin derivative.
 44. A polymeric film-formerfor coatings for a medical device, said polymer comprising a polyolefinderivative.